Bicyclo(3.2.1)octane amines as anti-influenza agents



United States Patent 3,439,101 BICYCLO[3.2.1]0CTANE AMINES ASANTI-INFLUENZA AGENTS Alfred W. Chow, Radnor, Pa., assignor to SmithKline &

French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania N0Drawing. Filed Aug. 9, 1966, Ser. No. 571,189 Int. Cl. A61k 27/00; C07c87/40 US. Cl. 424-325 8 Claims ABSTRACT OF THE DISCLOSUREBicyclo[3.2.1]octanes, substituted with an amino, aminomethyl, orvt-aminoethyl group, are prepared, formulated, and administered towarm-blooded mammals to combat influenza infections.

The present invention relates to amino derivatives ofbicyclo[3.2.1]octane and to methods of using said compounds toameliorate the effects of and prevent influenza infections.

The compounds of the present invention are characterized by thefollowing structural formulas:

where one A group is and the other A groups are hydrogen, and one Bgroup is CH NH and the other B groups are hydrogen.

The invention also includes a method of ameliorating the effects of andpreventing influenza infections comprising administering to an infectedwarm-blooded mammal or to such a mammal prior to infection an effective,but nontoxic, amount of a compound of the Formula H1 or apharmaceutically acceptable acid addition salt thereof.

6 3 C III where one C group is NH CH NH or r CHNHz 3,439,101 PatentedApr. 15, 1969 thoxymethyl triphenylphosphonium chloride and butyllithium in solvents such as tetrahydrofuran and diglyme. The resultingmethoxymethylene compound is then converted to the carboxaldehyde bymeans of a strong acid such as perchloric or hydrochloric acid, and thealdehyde oxidized to the carboxylic acid with silver nitrate. The acidsare then converted to the u-aminoethyl products by methods describedabove.

The various aminomethyl compounds of Formula 11 are prepared byconverting the appropriate carboxylic acid to an acid chloride,converting the acid chloride to the amide with aqueous or gaseousammonia, and reducing the amide with lithium aluminum hydride.

The other compounds which are part of the method or process aspect ofthe invention are prepared as follows:

The 2-amino compound is obtained as described in German Patent1,167,337.

The 3, 6, and S-amino compounds are prepared by converting the knownketones to their oximes, and then reducing the oximes to the aminescatalytically or with lithium aluminum hydride.

The amine compounds of the invention are readily converted to acidaddition salts by conventional methods, including addition of the acidin pure form or as an ethereal, alcoholic, or acetone solution to thefree base, which may also be in solution. The salts of these bases withpharmaceutically acceptable acids, being merely more convenient, moresoluble, or more stable forms of the physiologically active bases, arethe full epuivalents of said bases. Exemplary of the pharmaceuticallyacceptable acids are hydrochloric, hydrobromic, sulfuric, maleic,succinic, and tartaric acids.

The compounds of the invention are active at dose levels of 625-100 mg./kg. They are used and the methods of the invention are practiced byformulating the compounds into pharmaceutical compositions in theconventional manner and administering them to a warm-blooded mammalinfected with or susceptible to influenza viruses, particularly type AThe 2-amino compound has been found to cause a 40-95% increase in thesurvival of mice infected with Asian influenza at subcutaneous doses of6.25100 mg./kg. The 3-amino compound causes a 30'- 50% increase at 100mg./ kg, and the 8-amino compound causes a 4555% increase at 25 m.g./kg.The preferred compositions are tablets and capsules to be administeredorally and suspensions and solutions to be administered intranasally.These compositions may include such standard excipients as lactose,starch, terra alba, magnesium stearate, calcium sulfate, glycerol monoor distearate, gelatin, or wax. The oral compositions may contain 50-500 mg. of intiviral compound or salt thereof, and may be administeredeither as one dose or in divided doses. The intranasal preparation maybe a 210% solution or suspension and may be a spray or nose drops.

It will be apparent to one skilled in the art of medicinal chemistrythat certain obvious variants in the compounds and methods of thepresent invention may be introduced without departing from the spiritthereof. Such variants include lower alkyl and acyl derivatives of theamines, as well as amine oxides and quaternary salts. Such variants areprepared by standard alkylation, acylation, oxidation, andquaternization reactions and so far as they possess the same propertiesare the full equivalents of the claimed compounds.

EXAMPLE 1 Bicyclo [3 .2. l octan-Z-amine To g. of H 50 is added dropwiseat ill-15 14 ml. of CH CN, followed by 31.0 g. (0.245 mole) of bicyclo-[2.2.1]heptane-Z-methanol [Beta 71, 1939 (1938)]. The mixture is stirredfor 2 /2 hours at 20 and neutralized 3 with 10% NaOH (554 ml.), and the2-acetamidobicyclo[3.2.1]-octane intermediate extracted with benzene.The amide is crystallized from n-hexane to give M.P. of 133-134".

The amide (1 g., 0.0055 mole) is refluxed in conc. HCl under N for 20hours, and the solid obtained is recrystallized from CH CN to give thehydrochloride salt of the title product, M.P. 310. The free base isobtained by dissolving the salt in water, making the solution basic, andextracting with ether.

This procedure is similar to that described in German Patent 1,167,337.

EXAMPLE 2 Bicyclo [3.2.1] octan-3-amine To a solution of 16.3 g. (0.234mole) of NH OHHCI in 65 ml. of water is added 65 ml. of 10% NaOH and thepH is adjusted to 6.6. To this solution is added 6.5 g. (0.052 mole) ofbicyclo[3.2.1]octan-3-one [1. Org. Chem. 28, 2200 (1963)] dissolved in13 ml. of alcohol. The mixture is heated at 70 for 45 minutes and thencooled, and the white oxime precipitates.

This oxime (1 g., 0.0064 mole) is dissolved in 200 ml. of methanolcontaining some ethereal CH1 and 0.3 g. of PtO and hydrogenated at 60and 60 p.s.i. for 10 hours. Following evaporation, the hydrochloridesalt of the title amine is recrystallized from methanol-ether to giveMP. of 300 dec. The base is obtained in the usual manner.

EXAMPLE 3 Bicyclo [3 .2. 1 octan-6-amine A solution of 4.0 g. (0.032mole) of bicyclo[3.2.1]- octan-6-one [Rocz. chim. 36, 235 (1962)], 4.0g. of NH OH.HCl, and 16 g. of KOH in 80 ml. of 95% ethanol is refluxedfor 2 hours. The mixture is poured into ca. 500 ml. of water andneutralized to pH 6 with concentrated HCl. The mixture is then extractedwith ether and the ether extracts are dried and evaporated to give theintermediate oxime.

A mixture of 9.0 g. (0.064 mole) of the oxime and 3.6 g. of PtO in 300ml. of ethanol (containing 20 ml. of ethereal HCl) is hydrogenated at 60and 60 p.s.i. for 15 hours. The catalyst is filtered off, and thefiltrate evaporated in vacuo. The residue is dissolved in water,filtered, and made basic with 10% NaOH. The free amine is extracted withether and obtained upon drying and evaporating the solvent. The amine isdissolved in ether and ethereal HCl is added to give the hydrochloridesalt. Recrystallization from ethyl acetate-isopropanol gives a puresample, decomp. at 300.

EXAMPLE 4 Bicyclo [3 .2.1] octan-8-amine A solution of 2.5 g. (0.2 mole)of bicyclo[3.2.1]-octan- 8-one [Tetrahedron 20, 687 1964)], 1.7 g.(0.025 mole) of NH OHHCI, and 2.6 g. of pyridine in 50 ml. of alcohol isrefluxed overnight. After evaporation and recrystallization fromn-hexane, the intermediate S-oxime is obtained.

This oxime (0.9 g., 0.0064 mole) is dissolved in 200 ml. of methanolcontaining some ethereal HCl and 0.3 g. of PtO and hydrogenated at 60and 60 p.s.i. for 8 hours. After evaporation, the hydrochloride of thetitle amine is recrystallized from methanol-ether to give pure salt,M.P. 250 dec. The free base is obtained in the usual manner.

EXAMPLE u-Methylbicyclo [3 .2.1]octane-l-methylamineBicyclo[3.2.1]octane-1-carboxylic acid (4.71 g., 0.0306 mole) isdissolved in 100 ml. of dry tetrahydrofuran and, with stirring undernitrogen, 31 ml. (0.062 mole) of 2 N methyl lithium in ether is addedover 3 to 4 minutes. The mixture is refluxed overnight and cooled toroom temperature. Water (25 ml.) is added, and the product extractedinto ether. After drying over MgSO the ether is removed to givebicyclo[3.2.1]oct-l-yl methyl ketone.

To a mixture of 5.5 g. of the ketone, 3.22 g., (0.0463 mole) of NHOH.HCl, and 15 ml. of ethanol are added, portionwise with stirring, 3ml. of Water and 5.9 g. of powdered NaOH. The reaction mixture isstirred and refluxed for 5 minutes and then poured into an ice coldsolution of 20 ml. of concentrated HCl in ml. of water. The colorlesssolid is filtered and washed with water. By drying over P 0 the oxime isobtained.

A mixture of 5.35 g. (0.032 mole) of the oxime and 1.8 g. of PtO in ml.of ethanol (containing 10 ml. of ethereal HCl) is hydrogenated at 60 and60 p.s.i. for 15 hours. The catalyst is filtered off and the filtrateevaporated in vacuo. The residue is dissolved in water, filtered, andmade basic with 10% NaOH. The free product amine is extracted withether. Drying and evaporation gives the product. The amine is dissolvedin ether and ethereal HCl is added to precipitate the hydrochloride saltof the amine; purification is achieved by recrystallization.

The corresponding 0: methylbicyclo[3.2.1]octane-2- methylamine isprepared in the same manner from the 2-carboxylic acid.

EXAMPLE 6 a-Methylbicyclo 3 .2. 1 octane-6-methylamine A stirredsuspension of methoxymethyl triphenyl phosphonium chloride (40 g., 0.117mole) in tetrahydrofuran (200 ml.) is treated dropwise with etherealbutyl lithium (105 ml., 0.10 mole) in a nitrogen atmosphere and allowedto stir at 25 for 3 hours. To the resulting deep red solution is addeddropwise a solution of bicyclo[3.2.l]octan-6-one (6.2 g., 0.05 mole) intetrahydrofuran (40 ml.) and diglyme (40 ml.). After stirring 4 hours at25 the tetrahydrofuran is removed by heating on a steam bath. Diglyme(200 ml.) is added and the mixture heated at reflux for 7 hours. Themixture is then cooled, concentrated to one-half volume in vacuo, andtreated with methyl bromoacetate to remove any triphenylphosphine. Afterstanding 12 hours, the solid is filtered OE and the filtrate washed withwater. Evaporation of the dry organic layer gives, after alumina columnchromatography, 3-methoxymethylene bicyclo[3.2.l]octane.

This vinyl ether is allowed to stand 15 minutes at room temperature in asaturated solution of ether in HClO poured into aqueous NAHCO andextracted with ether. Evaporation of the dried ether layer gives the6-carboxaldehyde.

To a solution of 2.48 g. (0.018 mole) of this aldehyde and 11.32 g. ofAgNO in a mixture of 45 ml. of water and 35 m1. of absolute ethanol isadded, dropwise with stirring over a 2 hour period, a solution of 4.2 g.of NaOH in 75 ml. of water. The resulting mixture is stirred overnight,filtered, extracted with ether, acidified, and again extracted withether. Drying and evaporation of the ether gives the 6-carboxylic acid,which is converted to the title product by procedures described inExample 5.

Bicyclo[3.2.l] octan-8-one is correspondingly converted to itscarboxylic acid by the procedures described above.Bicyclo[3.2.1]octane-3-carboxylic acid is prepared by the proceduregiven in Annalen 692, 51 (1966). They are then converted to aa-methylbicyclo[3.2.1]octane-8- methylamine anda-methylbicyclo[3.2.1]octane-3-methylamine, respectively, by proceduresdescribed in Example 5.

EXAMPLE 7 Bicyclo[3.2.1]octane-1-methylamine A solution ofbicyclo[3.2.1]octane-1-carboxylic acid (5. g.) in S001 (25 ml.) isrefluxed for 1 hour and then allowed to stand overnight at roomtemperature. The excess SOC1 is removed in vacuo, the residual oil istaken up in benzene ml.), and the solution evaporated in vacuo to givethe acid chloride as an oil.

The crude acid chloride is dissolved in dry tetrahydrofuran ml.) and thesolution added dropwise during 2-3 minutes to an ice-cold solution ofconcentrated NH OH (75 ml.). After stirring 1 hour, water (25 ml.) isadded, and the precipitated l-carboxamide collected by filtration.

To a slurry of LiAlH (3 g.) in boiling tetrahydrofuran (400 ml.) isadded portionwise over 1 hour 3 g. of the above amide, all undernitrogen. The mixture then is heated at reflux for 46 hours, cooled, andexcess LiAlH decomposed by dropwise addition of saturated aqueous Na SOThe resulting white slurry is filtered, the filter cake washed withether, and the combined filtrates evaporated in vacuo. The liquidresidue is boiled with ether and the ether layer dried. Evaporation ofthe ether gives the title l-aminomethyl product. Treatment of an ethersolution of the product with ethereal HCl gives a hydrochloride saltwhich is purified by recrystallization.

Bicyclo[3.2.l]octane 2 methylamine, bicyclo[3.2.1] octane-S-methylamine,bicyclo[3.2.l]octane 6 methylamine, andbicyclo[3.2.1]octane8-methylamine are all prepared in the same mannerfrom the corresponding carboxylic acids.

I claim:

1. A method of preventing influenza infection comprising administeringto a warm-blooded mammal an effective, but nontoxic, amount of acompound of the formula 6 Where one C group is NH CH NH or and the otherC groups are hydrogen, or a pharmaceutically acceptable acid additionsalt thereof.

2. A method as claimed in claim 1, Where one C group is NH and the otherC groups are hydrogen.

3. A method as claimed in claim 2, where the C group at the 2-positionis NH and the other C groups are hydrogen.

4. A method as claimed in claim 1, where the C group at the 2-positionis CH NH and the other C groups are hydrogen.

5. An oral dosage unit in the form of a tablet or capsule for theprevention of influenza infections in warm-blooded mammals comprising-500 mg. of a compound as defined in claim 1 and a pharmaceuticalcarrier.

6. An oral dosage unit in the form of a tablet or capsule for theprevention of influenza infections in warm-blooded mammals comprising50500 mg. of a compound as defined in claim 2 and a pharmaceuticalcarrier.

7. An oral dosage unit in the form of a tablet or capsule for theprevention of influenza infections in Warm-blooded mammals comprising50-500 mg. of a compound as defined in claim 3 and a pharmaceuticalcarrier.

8. An oral dosage unit in the form of a tablet or capsule for theprevention of influenza infections in warm-blooded mammals comprising50-500 mg. of a compound as defined in claim 4 and a pharmaceuticalcarrier.

References Cited FOREIGN PATENTS 1,167,337 4/1964 Germany.

ALBERT T. MEY'ERS, Primary Examiner.

I. GOLDBERG, Assistant Examiner.

